Process for the manufacture of therapeutically valuable compounds of kerating degradation products



Patented Apr. 1, 1941 PROCESS FOR THE MANUFACTURE OF THERAPEUTICALLY VALUABLE COM- POUNDS OF KERATIN DEGRADATION PRODUCTS Karl Schiillkopf, Berlin-Dahlem, Germany, as-

signor to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing.

Application December 21, 1937,

Serial No. 180,944. In Germany December 23,

26 Claims.

This invention relates to a process for the manufacture of therapeutically valuable gold compounds of keratin degradation products, and is an improvement in or modification of that described U. S. application Serial No. 99,960, now Patent No. 2,197,795, issued April 23, 1940; and relates further to the production of alkaline earth metal compounds of gold and gold-free keratinic acids.

According to the process of U. S. application Serial No. 99,960 therapeutically valuable gold compounds of keratin degradation products are obtained by reacting gold keratinic acids, which are obtained in known manner by acid hydrolysis or gentle acid hydrolysis in combination with enzymatic digestion of keratins, with or without simultaneous or subsequent reduction, and treatment with gold salts, with oxides, hydroxides or carbonates of the alkaline earths, including magnesium, and the water soluble alkaline earth gold keratinates thus obtained precipitated from the aqueous solution by means of alcohol or other organic solvents miscible with water.

According to one feature of the present invention the same compounds are obtained when the alkali metal salts of gold keratinic acids are caused to interact with the water soluble salts of the alkaline earth metals, in particular of calcium or magnesium.

According to a further feature of this invention the desired compounds are also obtained when gold compounds are caused to react in the manner known per se on the alkaline earth metal keratinates. The alkaline earth metal keratinates (by which term I include also the magnesium compounds) to be employed in this case as starting materials are new compounds and are obtained in accordance with the invention from keratin degradation products produced in known manner which have been obtained by hydrolysis of keratins such as hair, wool, horn, feathers and the like, for example, by means of acids, such as dilute hydrochloric acid, or by means of acids and proteolytic enzymes with or without simultaneous or subsequent reduction, for example, with tin in acid solution. The hydrolysis mixtures obtained in the hydrolysis of keratins are treated, if desired after removal of the reducing agent, for example, with hydrogen sulfide when heavy metals have been employed as reducing agents,

with the alkaline earth metal compounds, as, for example, in the case of the application of acid hydrolysis, with the hydroxides, oxides or carbonates of the said metals, to neutral or weakly alkaline reaction and the compounds thus obtained separated in the manner known per se, for example, by precipitation with organic liquids miscible with water as, for example, alcohol, acetone and the like. In this case it is to be recommended if the hydrolysis of the keratin substances was carried out by means of acids, prior to addition of the alkaline earth metal or magnesium compounds, to neutralize the acids employed in excess for the hydrolysis with basic substances, suitably with ammonia.

This latter process can also be carried out in such a manner that, after the hydrolysis of the keratins, first the alkali metal compounds are produced and these caused to react with the water soluble salts of the alkaline earth metals.

Finally according to a still further feature of this invention also starting from the keratin degradation products or the keratinic acids themselves it is possible by simultaneous action of gold compounds and the oxides, hydroxides or carbonates of the alkaline earth metals, including magnesium, to produce the desired alkaline earth metal gold keratinates.

The compounds obtained can be precipitated from the reaction solution by means of suitable organic solvents miscible with water as, for example, ethanol, methanol or acetone.

They can if desired be purified by further dis solving in water with renewed precipitation with the specified agents.

The following examples serve to illustrate the invention without, however, limiting the same to them:

Example 1 300 grams of hair are hydrolyzed by heating with 1200 ms; of 20% hydrochloric acid in a water bath at 95 Offer 1 hour. T'hereupon 30 grams of tin foil are introduced and the whole heated for a further hour on the water bath at 95 C. with frequent shaking. Then after cooling at 20 C. the acid hydrolysate is partially neutralized with 500 ccs. of 25% ammonia to a weakly acid reaction, the tin is precipitated as tin sulphide by introduction of hydrogen sulphide and separated off by suction. After driving off the hydrogen sulphide dissolved in the filtrate by introduction of hydrogen there are introduced into the filtrate gradually with stirring 103 ccs. of a 20% aqueous solution of gold chloride hydrochloride (50% gold content) and the whole rendered weakly alkaline with caustic soda lye. On stirring the solution thus obtained into 5 times the quantity of alcohol the sodium salt of the gold keratinic acid is precipitated as a viscous oily product. After 24 hours product. is decanted from the oily residue and the latter dissolved in 3'75 cos. of water. added a solution of 30 grams of magnesium sulstanding the alcohol is decanted from the oily sediment and the latter dissolved in 375 ccs. of water. To. this solution is added a solution of 28 grams of calcium chloride in 100 ccs. of water, the whole is filtered and by stirring of the filtrate into 6 times the quantity of alcohol the calcium 1 salt of gold keratinic acid precipitated as a fiocculent product. It is filtered with suction and washed with alcohol and ether. It is freed from adhering diflicultly soluble impurities by repeated precipitation from aqueous solution with alcohol. The calcium salt of the gold keratinic acid is obtained as a slightly yellowish powder easily soluble in water and contains 5.1% Ca and 14.4% Au.

Example 2 10 grams oi a sodium gold keratinate are dissolved in 100 cos. of water and a solution of 5 1 grams of calcium chloride in 20 cos. of water introduced. After filtration of the mixed solution. the filtrate is stirred into 6 times the quantity of alcohol and the precipitated calcium salt washed I tic sola lye and filtered from insoluble portions. 3 To the filtrate are then gradually added with stirring 135 ccs. of a 20% aqueous solution of gold chloride hydrochloride, whereby the gold keratinic acid produced is precipitated. The latter is g thereupon dissolved by the addition of caustic soda lye to weak alkaline reaction and the solugrams of calcium hydroxide and filtered. The filtrate is stirred into 6 times the quantity of alcohol, whereby the calcium keratinate precipitates and settles on the bottom as a solid but still somewhat sticky mass. Alter decanting the alcohol from the residue the latter is dissolved in 1 liter of water. This solution is treated with 180 cos. of 20% sodium aurichloride solution gradtion obtained stirred into 6 times the volume of alcohol whereby the sodium salt 01' the gold keratinic acid is precipitated as a viscous oily After several hours stirring the alcohol To this solution is phate in 150 ccs. of water, the whole is filtered I and the magnesium salt of the gold keratinic acid precipitated by stirring the filtrate into 8 times the volume of alcohol. The product is filtered with suction, washedwith alcohol and ether and dried. The magnesium salt of the gold keratinic acid is obtained as a white powder easily soluble in water and contains 3.8% Mg. and 11% Au.

Example 4 300 grams of hair are worked up as in Example 1 to the aqueous solution of the sodium salt of the gold keratinic acid. To this solution is then added a solution of 30 grams of strontium chloride in .150 cos. of water, the whole filtered and the strontium salt of the gold keratinate precipitated i All.

Example 5 300 grams of hair are hydrolyzed with 1200 ccs.

of hydrochloric'acid by heating in a water bath at 95 C. for 1% hours. The hydrolysate is thereupon after cooling to 20 C. partially neutralized with 500 ccs. of ammonia, the still weakly acid mixture rendered alkaline with ually with stirring. The'whole is then filtered from a slight precipitate thereby produced, the

filtrate stirred into 8 times the quantity of alcohol, the precipitated calcium salt of the gold keratinic acid washed with alcohol and ether and dried in vacuum. It is obtained as a slightly yellowish powder easily soluble in water nd contains 5.5% Ca and 11.6% Au.

Example 6 300 grams of hair are heated for 1 hour with 1200 ccs. of 20% hydrochloric acid in a water bath at C. then to the hydrolysate 300 grams of tin foil added and the whole further heated for A hour. After cooling of the hydrolysate it is partially neutralized to a weakly acid reaction with 25% ammonia, the tin separated as tin sulphide by introduction of hydrogen sulphide and filtered of! with suction and thereupon in the filtrate the hydrogen sulphide completely removed by evacuation or driving oil by means of an indifierent gas as, for example, nitrogen; Into the sulphhydryl keratinic acid solution thus obtained are then introduced 48 grams of magnesium carbonate to a neutral reaction and the solution obtained stirred into 12 times the volume of alcohol 7 whereby the magnesium salt of the sulphhydryl keratinic acid separates. After separation from alcohol the magnesium keratinate is dissolved in 1 liter of water, to this solution 138 ccs. of a 20% aqueous gold chloride hydrochloride gradually added and the hydrochloric acid thereby liberated combined to a neutral or weakly alkaline reaction by gradual addition of 18 grams of magnesium carbonate. Thereupon small quantities of insoluble products are filtered oil and the filtrate stirred into 8 times the volume of alcohol, whereby the magnesium salt of' the gold sulphhydryl keratinic acid precipitates which is filtered with suction, washed with alcohol'and ether and dried in vacuum at 60 C. The light yellow substance obtained has a content of 4.4% Mg and 17.4% Au.

Example 7 To a solution of 40 grams of a sulphhydryl keratinic acid in 200 ccs. of water are gradually added with stirring 40 cos. of a 20% gold chloride hydrochloride and at the same time so much magnesium carbonate is introduced that the reaction of the solution remains neutral although after completion of the addition of the gold chloride hydrochloride solution a pH=7.4 is indicated. The whole is filtered from the small precipitate. the filtrate stirred into 10 times the quantity of alcohol, the magnesium salt of the gold sulphhydryl keratinic acid thereby precipitated, filtered with suction, washed with alcohol and ether and dried in vacuum. It is obtained as a lightly yellow colored powder easily soluble in water and contains 2.4% Mg and 10.6% Au.

Example 8 grams of a keratin degradation product which has been obtained by hydrolysis of hair with 30% sulphuric acid on the water bath.up to solution, dialysis of the hydrolysate and evaporation of the dialysate obtained to dryness, are dissolved in 1 liter of water and to this solution -ccs. of a 20% aqueous gold chloridehydrochloride are gradually added with stirring and at the same time so much calcium hydroxide introduced that the reaction after the addition of the gold chloride hydrochloride is weakly alkaline. After filtration of the solution by precipitation with alcohol the calcium salt of the gold keratinic acid is isolated and the latter, for purification from small diflicultly soluble constituents, again precipitated from aqueous solution. The practically white calcium salt thus obtained contains about 5.5% Ca and Au.

Of course, many changes and variations in the reaction conditions and the like may be employed 'by those skilled in the art in accordance with the principles set forth herein.

What I claim is:

1. Process for the manufacture of alkaline earth metal salts of gold keratinic acids, such as may be obtained by the degradation of keratins followed by interaction with a gold salt and neutralization with a basic reacting alkali metal compound, comprising reacting said alkali metal salts of the gold keratinic acids with a water soluble salt of and alkaline earth metal.

2. Process for the manufacture of alkaline earth metal salts of gold keratinic acids, such as may be obtained by reduction of degraded keratins followed by interaction with a gold salt and neutralization with a basic reacting alkali metal compound, comprising reacting said alkali metal salts of the gold keratinic acids, with a water soluble salt of an alkaline earth metal.

- 3. Process as claimed in claim 1, in which as alkaline earth metal compound a calcium compound is employed.

4. Process as claimed in claim 1, in which the gold keratinate of said alkaline earth metal is separated from the aqueous solutions by means of an organic liquid miscible with water.

5. Process for the manufacture of alkaline earth metal keratinates from keratin degradation products which are obtained by hydrolysis of keratins by means of acids, wherein the hydrolysis mixture is treated with an alkaline earth metal compound and the compounds thus obtained separated by precipitation with an organic liquid miscible with water.

6. Process as claimed in claim 5, after which in the hydrolysis of the keratins first the alkali metal compounds are produced and these caused to react with the water soluble salts of the said alkaline earth metal.

7. An alkaline earth metal salt of the reduced hydrolyzation products of a keratinous material.

8. An alkaline earth metal salt of the unreduced hydrolyzation products of a keratinous material.

9. A calcium salt of the reduced hydrolyzation products of a keratinous material.

10. Process for the manufacture of therapeutically valuable salts of keratinic acids, which comprises reacting a compound containing a keratinate radical with a compound .of an alkaline earth metal capable of entering into double decomposition therewith.

11. Process for the manufacture of therapeutically valuable salts of keratinic acids, which comprises reacting a compound of the group consisting of keratinic acids and gold keratinic acids with a compound of an alkaline earth metal capable of entering into double decomposition therewith.

12. Process according to claim 11, wherein the keratinic acid is contained in the reaction prodact of a gold compound and the product of the acid hydrolysis of keratins.

13. Process according to claim 10, wherein the metal keratinate reaction product is reacted with a gold compound.

14. Process according to claim 13, wherein the metal keratinate reaction product is reacted with a gold compound and wherein the keratinic acid is subjected to reduction prior to reaction with the metal compound.

15. Process according to claim 11, wherein the acid is neutralized with a basic reacting alkali metal compound prior to reaction with the alkaline earth metal compound. said compound being capable of entering into double decomposition with the alkali metal keratinate.

16. Process according to claim 11, wherein the acid is neutralized with a basic reacting alkali metal compound prior to reaction with the alkaline earth metal compound, said compound being capable of entering into double decomposition with the alkali metal keratinate, and wherein the acid is subjected to reduction prior to reaction with the alkaline earth metal compound.

1'7. Process according to claim 11, wherein the keratinic acid is contained in the reaction product of a gold compound and the product of the acid hydrolysis of keratins, and wherein the alkaline earth metal compound is a member of the group consisting of the oxide, hydroxide and carbonate.

18. Process according to claim 11, wherein the metal compound is a member of the group consisting of the oxide, hydroxide and carbonate, and is employed in such amount that at least the neutral condition is reached.

19. The magnesium compound of a reduced keratinic acid.

20.,An approximately neutral alkaline earth metal keratinate which is substantially completely insoluble in alcohol.

21. A calcium keratinate product which is substantially completely insoluble in alcohol.

22. The isolated calcium compound of a reduced keratinic acid, said compound being sub- 

